Acute myeloid leukaemia niche regulates response to L-asparaginase

Ilaria M. Michelozzi, Valentina Granata, Giada De Ponti, Gaia Alberti, Chiara Tomasoni, Laura Antolini, Carlo Gambacorti-Passerini, Bernhard Gentner, Francesco Dazzi, Andrea Biondi, Tiziana Coliva, Carmelo Rizzari, Alice Pievani, Marta Serafini

Research output: Contribution to journalArticlepeer-review

Abstract

Eradicating the malignant stem cell is the ultimate challenge in the treatment of leukaemia. Leukaemic stem cells (LSC) hijack the normal haemopoietic niche, where they are mainly protected from cytotoxic drugs. The anti-leukaemic effect of L-asparaginase (ASNase) has been extensively investigated in acute lymphoblastic leukaemia, but only partially in acute myeloid leukaemia (AML). We explored the susceptibility of AML-LSC to ASNase as well as the role of the two major cell types that constitute the bone marrow (BM) microenvironment, i.e., mesenchymal stromal cells (MSC) and monocytes/macrophages. Whilst ASNase was effective on both CD34+ CD38+ and CD34+ CD38- LSC fractions, MSC and monocytes/macrophages partially counteracted the effect of the drug. Indeed, the production of cathepsin B, a lysosomal cysteine protease, by BM monocytic cells and by AML cells classified as French-American-British M5 is related to the inactivation of ASNase. Our work demonstrates that, while MSC and monocytes/macrophages may provide a protective niche for AML cells, ASNase has a cytotoxic effect on AML blasts and, importantly, LSC subpopulations. Thus, these features should be considered in the design of future clinical studies aimed at testing ASNase efficacy in AML patients.

Original languageEnglish
Pages (from-to)420-430
Number of pages11
JournalBritish Journal of Haematology
Volume186
Issue number3
DOIs
Publication statusPublished - Aug 1 2019

Keywords

  • acute myeloid leukaemia
  • asparaginase
  • bone marrow microenvironment
  • cathepsin B
  • leukaemic stem cells

ASJC Scopus subject areas

  • Hematology

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